Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant forms of the human thromboxane A2 (TXA2) receptor composed of the carboxyl-terminal amino acid residues 220-343 were phosphorylated in vitro by both cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC), and these phosphorylations were competed for by synthetic peptides corresponding to the proposed carboxyl-terminal cytoplasmic tail and/or the third extracellular loop of the receptor, respectively. Exogenous addition of PKA or PKC to membrane preparations of human embryonic kidney 293 cells, transfected with the TXA2 receptor, typically reduced TXA2 receptor binding by 10 and 30%, respectively. In vivo inhibition of PKC or PKA in the transfected human embryonic kidney 293 cells increased TXA2 receptor binding to 121.4% (+/- 5.3%) and 110.4% (+/- 4.6%), respectively, relative to control cells. In vivo activation of PKC in the platelet-like human erythroleukemia (HEL) cells by the phorbol ester phorbol 12-myristate 13-acetate (PMA) resulted in an initial reduction followed by a time-dependent increase in TXA2 receptor ligand binding. Stimulation of HEL cells with the TXA2 receptor agonist [15-(alpha,2 beta(5Z)-3 alpha(E,3S)-4 alpha)]-7-[3- (3-hydroxy-4-(p-iodophenoxy)-1-butenyl)-7-oxabicyclo-[-2.2,1-]hept -2-yl]- 5-heptenoic acid or basic fibroblast growth factor, alone or together, resulted in a marked decrease in TXA2 receptor binding. Northern blot studies in HEL cells demonstrated that PMA stimulation induced the expression of the TXA2 receptor gene with mRNA levels peaking following PMA stimulation for 4-8 h. This induction is consistent with the presence of a phorbol ester response element in promoter I of the TXA2 receptor gene. Dexamethasone did not induce the expression of the receptor gene, despite the presence of a glucocorticoid response element in promoter II of the TXA2 receptor gene. In summary, our results indicate that the cellular responses to TXA2 are mediated both by phosphorylation of the TXA2 receptor by different protein kinases and by regulated expression of the TXA2 receptor gene.
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PMID:Phosphorylation and regulated expression of the human thromboxane A2 receptor. 796 88

Murine erythroleukemia (MEL) cells deficient in cAMP-dependent protein kinase (A-kinase) activity are impaired in chemically induced differentiation (Pilz, R. B., Eigenthaler, M., and Boss, G. R. (1992) J. Biol. Chem. 267, 16161-16167). We identified by two-dimensional polyacrylamide gel electrophoresis two low molecular weight proteins (referred to as pp 21-1 and 21-2) that were phosphorylated when parental MEL cells, but not A-kinase-deficient MEL cells, were treated with the membrane-permeable cAMP analog 8-bromo-cAMP. We showed that pp 21-1 and 21-2: (a) were direct A-kinase substrates; (b) bound GTP; and (c) belonged to the ras superfamily of proteins. The only ras-related proteins that are clearly A-kinase substrates both in vitro and in vivo are Rap 1A and 1B while H- and K-Ras can be A-kinase substrates in vitro; we showed by immunological methods, phosphopeptide mapping, and migration on two-dimensional gels that pp 21-1 and 21-2 were not identical to one of these four proteins. We found a 3-fold increase of 32PO4 incorporation into pp 21-2 in hexamethylene bisacetamide-treated parental MEL cells which was not secondary to an increase in pp 21-2 protein but appeared secondary to increased phosphorylation of pp 21-2 by A-kinase. Thus, pp 21-1 and 21-2 are either new ras-related proteins or are previously identified ras-related proteins not known to be A-kinase substrates, and increased phosphorylation of pp 21-2 occurs during differentiation of MEL cells.
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PMID:Identification of a ras-related protein in murine erythroleukemia cells that is a cAMP-dependent protein kinase substrate and is phosphorylated during chemically induced differentiation. 803 8

p18 is a phosphoprotein that is expressed at very high levels in leukemic cells, at moderately high levels in proliferating normal lymphocytes, and at low levels in quiescent lymphocytes. Induction of terminal differentiation of leukemic cells in culture results in a decrease in cellular proliferation. These phenotypic changes are associated with rapid phosphorylation of p18, followed by a more gradual decrease in the level of its mRNA expression. More than 12 different phosphorylation products of p18 have been identified in different cells by high resolution two-dimensional polyacrylamide gel electrophoresis. Previous studies have suggested that p18 may be a substrate for protein kinase C in some cellular processes and protein kinase A in others. In this report, we show that the phosphorylation of p18 increases as cells progress toward the G2-M phases of the cell cycle in proliferating leukemic cells. We have examined the hypothesis that the putative role of p18 in cellular proliferation may be mediated by its involvement in the p34cdc2 kinase signal transduction pathway. We have produced recombinant p18 in bacterial cells and shown that it can be phosphorylated in vitro by purified p34cdc2 kinase with a stoichiometry of 0.86 mol of PO4/mol of substrate. We have used site-directed mutagenesis to demonstrate that the site of p34cdc2 phosphorylation is the serine at position 38. This same site has previously been shown to be phosphorylated in vivo in bovine brain along with another serine at position 25. The observation that p18 gets phosphorylated in the G2-M phases of the cell cycle and the demonstration that p18 is phosphorylated efficiently by p34cdc2 kinase in vitro at a residue that is also phosphorylated in vivo support the hypothesis that p18 may be a physiologic substrate for p34cdc2 kinase in vivo. We have also examined the effect of inhibiting the expression of p18 on cell cycle progression. These experiments demonstrated that antisense inhibition of the expression of p18 in K562 erythroleukemia cells is associated with a decrease in cellular proliferation and accumulation of cells in the G2-M phases of the cycle. The implications of these findings to the proposed role of p18 in the regulation of cellular proliferation are discussed.
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PMID:Regulation of phosphoprotein p18 in leukemic cells. Cell cycle regulated phosphorylation by p34cdc2 kinase. 814 11

The Raf-1 protein, a cytoplasmic serine/threonine kinase, plays an important role in signal transduction pathways. In order to examine the role of Raf-1 in human myeloid leukemia, we determined raf-1 mRNA expression by Northern blot analysis in blast cell samples from 27 acute myeloid leukemia (AML) cases and peripheral blood mononuclear cells from six healthy donors. A normal raf-1 transcript size was detected in all cases investigated. However, overexpression of raf-1 mRNA was found in 2 of 27 AML cases, both of which were erythroleukemias (AML, FAB M6).
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PMID:Overexpression of the Raf-1 proto-oncogene in human myeloid leukemia. 820 58

Murine erythroleukemia cells rendered deficient in cAMP-dependent protein kinase (A-kinase) activity by gene transfection are severely impaired in hexamethylene bisacetamide (HMBA)-induced differentiation (Pilz, R. B., Eigenthaler, M., and Boss, G. R. (1992) J. Biol. Chem. 267, 16161-16167). We now demonstrate that the A-kinase-deficient cells produce hemoglobin normally in response to exogenous hemin and that the heme precursor delta-aminolevulinate (delta-ALA) significantly increases HMBA-induced synthesis of heme and globin chains in these cells; these data suggest that impaired heme synthesis is at least partially responsible for the cells' deficient hemoglobin synthesis. HMBA-induced expression of the erythroid-specific delta-ALA synthetase, porphobilinogen deaminase, and beta-globin mRNAs was less in A-kinase-deficient cells than in parental cells and was reduced in proportion to the cells' residual A-kinase activity; relative transcription rates of these genes were reduced concordantly. Impaired expression of these three erythroid-specific genes was a feature of many independently-derived A-kinase-deficient clones, and normal expression was found in transfectants with normal A-kinase activity. The A-kinase-deficient cells did not exhibit a generalized defect in gene regulation since mRNA expression and transcription rates of H- and L-ferritin, c-myc, c-myb, and several housekeeping enzymes were similar in HMBA-treated parental and A-kinase-deficient cells. Our data suggest that A-kinase may be involved in regulating genes with erythroid-specific promoters and provide further evidence for heme as a regulator of globin chain synthesis.
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PMID:Impaired erythroid-specific gene expression in cAMP-dependent protein kinase-deficient murine erythroleukemia cells. 837 86

Induction of maturation in Friend erythroleukemia cells is accompanied by a programmed cessation in cell proliferation and a concomitant increase in hemoglobin production. To investigate the role of protein kinase activity in the initiation of Friend erythroleukemia cell differentiation, autoradiographs of one-dimensional, nondenaturing gels were prepared from Friend erythroleukemia cells either untreated or preincubated with dimethyl sulfoxide (DMSO) or aphidicolin for a 30-min period. Extracts were treated with cAMP or cGMP prior to electrophoresis and assayed for protein kinase activity in the presence of endogenous or exogenously added histone substrates. The data demonstrated differences in protein kinase activity following exposure of Friend erythroleukemia cells to either DMSO or aphidicolin for 30 min. These changes in enzyme activity varied with the treatment of the cells and the substrate used. Two sets of protein kinases, one responsive to cAMP and the other responsive to cGMP, were activated in control cultures. A different cAMP-responsive enzyme was active only in differentiating cells. Another protein kinase, activated by cGMP, was associated with both DMSO and aphidicolin treatment. All of these protein kinases had a histone substrate preference. One noncyclic nucleotide activated protein kinase phosphorylating endogenous substrates was associated only with DMSO-induced cells. These findings suggest a multifaceted role for protein kinases early in the maturation of Friend erythroleukemia cells.
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PMID:Changes in protein kinase activity within 30 min of induced differentiation in Friend erythroleukemia cells. 839 52

Considerable progress has been made toward elucidating the pathway of induction of terminal differentiation of transformed cells by hybrid polar compounds such as hexamethylene bisacetamide (HMBA). HMBA alters factors controlling G1-to-S phase transition, leading to G1 arrest and inhibition of DNA synthesis. Among the inducer-mediated changes, suppression of cyclin-dependent kinase cdk4, which may be required for phosphorylation of the retinoblastoma protein pRB and perhaps p107, is critical in the pathway of terminal differentiation. HMBA induces an increase in the level of p21 which inhibits cyclin-dependent kinase activity and, in turn, may cause cells to arrest in G1. p107 complexes with transcription factor E2F, which may alter E2F-dependent gene transcription. the relationship of the inducer-mediated changes in cyclins, cdks, cyclin-cdk inhibitors and transcription factors to the expression of differentiation-specific genes has not yet been established. The hybrid polar compounds are potent inducers of differentiation of a wide variety of transformed cells. HMBA has been shown to induce differentiation of neoplastic cells in patients. A second generation of hybrid polar compounds have been synthesized which are up to 1000 fold more potent than HMBA on a molar basis as inducers of murine erythroleukemia (MEL) cells and other transformed cells in vitro. The potential of these compounds as clinically useful inducers of differentiation of cancer cells is under study.
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PMID:Cell cycle regulatory proteins are targets for induced differentiation of transformed cells: Molecular and clinical studies employing hybrid polar compounds. 871 72

The predominant cAMP phosphodiesterase in human platelets is the low K(m) cGMP-inhibited phosphodiesterase (PDE 3A). We have isolated native PDE3A from platelets and human erythroleukemia (HEL) cells and studied its kinetics. The platelet and HEL cell enzymes hydrolyze cAMP with a K(m) = 0.5 microM. Incubation of cell supernatant with cAMP dependent protein kinase resulted in a rapid increase in activity within minutes, which resulted from a 2-fold decrease in K(m) with no increase in Vmax. HEL cells grown for 24 h in the presence of 50 microM forskolin, an adenylate cyclase activator, demonstrate further increase in PDE3A of 274% of control (p = 0.03). Cells incubated with forskolin and cycloheximide or actinomycin D demonstrated no increase suggesting that cAMP stimulates PDE3A synthesis by transcriptional regulation. The results indicate that cAMP affects both the short and long-term regulation of PDE3A. The latter effect may play a role in the developing hematopoietic cell and the cardiovascular system to regulate cAMP levels.
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PMID:Isolation and regulation of the cGMP-inhibited cAMP phosphodiesterase in human erythroleukemia cells. 903 67

Whilst searching for a mammalian homologue of the Drosophila glass gene we cloned a mouse cDNA whose deduced sequence encodes a 614 amino acid (aa) protein with ten Cys2-His2 (C2H2) zinc finger (Zf) motifs. Zfp64 is expressed in all developing and mature mouse tissues examined, except the mouse erythroleukemia (MEL) cell line. Zfp64 maps to the distal region of mouse chromosome 2 close to lens opacity 4 (Lop4), a semidominant cataract mutation. Sequence analysis shows that Zfp64 has multiple potential phosphorylation sites for casein kinase II (CK II), protein kinase C (PKC), tyrosine kinase (TK) and c-AMP- and c-GMP-dependent protein kinase (cA/GMPDPK).
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PMID:A search for a mammalian homologue of the Drosophila photoreceptor development gene glass yields Zfp64, a zinc finger encoding gene which maps to the distal end of mouse chromosome 2. 903 7

The erythroleukemia-inducing Friend spleen focus-forming virus (SFFV) encodes a unique envelope glycoprotein which allows erythroid cells to proliferate and differentiate in the absence of erythropoietin (Epo). In an attempt to understand how the virus causes Epo independence, we have been studying signal transduction pathways activated by Epo to determine if SFFV exerts its biological effects by constitutively activating any of these pathways in the absence of Epo. We previously demonstrated that Stat proteins, the downstream components of the Epo-induced Jak-Stat pathway, are constitutively activated in SFFV-infected cells. In this study, we demonstrate that SFFV also activates Raf-1, MEK and mitogen-activated protein (MAP) kinase, the downstream components of the Raf-1/MAP kinase pathway. This pathway was activated in cells infected with the polycythemia-inducing strain of SFFV, which induces both proliferation and differentiation of erythroid cells in the absence of Epo, as well as in cells infected with the anemia-inducing strain of the virus, which still require Epo for differentiation. Inhibition of Raf-1 by using antisense oligonucleotides led to a partial inhibition of the Epo-independent proliferation of SFFV-infected cells. Expression of the transcription factors c-Jun and JunB, but not c-Fos, was induced in SFFV-infected cells in the absence of Epo, suggesting that constitutive activation of the Raf-1/MAP kinase pathway by the virus may result in deregulation of AP-1 activity. We conclude from our studies that infection of erythroid cells with SFFV leads to the constitutive activation of signal transduction molecules in both the Jak-Stat and Raf-1/MAP kinase pathways and that both of these pathways must be activated to achieve maximum proliferation and differentiation of erythroid cells in the absence of Epo.
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PMID:Both the polycythemia- and anemia-inducing strains of Friend spleen focus-forming virus induce constitutive activation of the Raf-1/mitogen-activated protein kinase signal transduction pathway. 944 83


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